Freeze-thaw method for modifying stent coating

ABSTRACT

Methods are disclosed for controlling the morphology and the release-rate of active agent from a coating layer for medical devices comprising a polymer matrix and one or more active agents. The methods comprise exposing a wet or dry coating to a freeze-thaw cycle. The coating layer can be used for controlled delivery of an active agent or a combination of active agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 11/472,760,filed on Jun. 21, 2006, published as United States Patent ApplicationPublication No. 2008-0305141 A1 on Dec. 11, 2008, and issuing as U.S.Pat. No. 8,246,973 on Aug. 21, 2012, which is incorporated by referenceherein in its entirety, including any drawings.

TECHNICAL FIELD

The present invention relates generally to the field of medical devices,particularly implantable medical devices, and to methods for coatingsuch devices with layers comprising a polymer matrix and one or moreactive agents. More particularly, this invention pertains to methods forcontrolling the morphology of coating layers. This invention furtherpertains to methods for designing and controlling active agentrelease-rates from coating layers for medical devices.

BACKGROUND

In the area of medical devices, biomaterial research continues to searchfor new compositions and methods to improve and control the propertiesof the medical devices. This is particularly true for medical articlesthat are implantable within a subject, where predictable andcontrollable performance is essential to the successful treatment of asubject.

An example of an implantable medical device is a stent. Stents can actas a mechanical means to physically hold open and, if desired, expand apassageway within a subject. Typically, a stent is compressed, insertedinto a small vessel through a catheter, and then expanded to a largerdiameter once placed in a proper location. Stents play an important rolein a variety of medical procedures such as, for example, percutaneoustransluminal coronary angioplasty (PTCA), a procedure used to treatheart disease by opening a coronary artery blocked by an occlusion.Stents are generally implanted in such procedures to reduce occlusionformation, inhibit thrombosis and restenosis, and maintain patencywithin vascular lumens. Examples of patents disclosing stents includeU.S. Pat. Nos. 4,733,665; 4,800,882; and 4,886,062.

Stents are also being developed to locally deliver active agents, e.g.drugs or other medically beneficial materials. Local delivery is oftenpreferred over systemic delivery, particularly where high systemic dosesare necessary to affect a particular site. For example, agent-coatedstents have demonstrated dramatic reductions in stent restenosis ratesby inhibiting tissue growth associated with restenosis.

Proposed local delivery methods from medical devices include coating thedevice surface with a layer comprising a polymeric matrix and attachingan active agent to the polymer backbone or dispersing, impregnating ortrapping the active agent in the polymeric matrix. For example, onemethod of applying an active agent to a stent involves blending theagent with a polymer dissolved in a solvent, applying the composition tothe surface of the stent, and removing the solvent to leave a polymermatrix in which an active agent is impregnated, dispersed or trapped.During evaporation of the solvent, phase separation candisadvantageously occur, often resulting in hard-to-control processconditions and a drug coating morphology that is difficult to predictand control. This makes delivery of the agent unpredictable.

Further, manufacturing inconsistencies among different stents can arisewith the above coating method. For example, release-rate variability hasbeen observed among supposedly identical stents made by the sameprocess. Apparently, when some polymer coatings comprising active agentsdry on the surface of a medical device different morphologies develop indifferent coatings, even if the coating process parameters areconsistent. These differences in coating morphology may cause activeagent release-rates from different stents to vary significantly. As aconsequence of the inconsistent release-rate profiles among stents therecan be clinical complications. Thus, there is a need for methods thatcan control the variability of active agent release-rates among medicaldevices and provide manufacturing consistency.

Morphological changes that affect release-rates of active agents havebeen observed to be dependent on the active agent phase in the polymermatrix. When a coating composition is applied to the surface of amedical device the active agent is initially evenly dispersed in thecoating composition. However, during processing the agent may migrate orphase separate to form different phase regions within the coating layer.These regions are often connected with each other and are referred to asthe percolation phase. The mass transport properties of active agentsare distinct through the percolation phase. Mass transport through thepercolation phase is driven by the solubility of active agent in therelease medium, the diffusivity of the active agent in the releasemedium, and the morphological feature of the percolated phase such as,for example, tortuosity and area fraction. The release-rate of theactive agent is often greatly increased from these regions or phases.The formation of percolated phases is particularly pronounced at highactive agent concentrations, for example above about 35% by volumefraction of active agent to polymer in the coating layer. The actualvolume percent will vary and depends greatly on the aspect ratio andmorphology of the active agent as well as the nature of the surroundingpolymer.

Those skilled in the art will therefore appreciate that local deliverywould benefit not only from improved release-rate profiles that arecontrolled and predictable, but also from manufacturing improvementsthat would provide consistency. Thus, methods for making coated medicaldevices with more reliable performance are highly desirable andessential to providing effective treatment of patients. In addition,control over the release-rate can assist in designing and maintainingthe physical and mechanical properties of medical devices and coatings,as well.

SUMMARY

Methods are disclosed for controlling the morphology and therelease-rate of active agent from coating layer(s) for medical devicescomprising a polymer matrix and one or more active agents. The methodscomprise exposing a wet or dry coating to a freeze-thaw cycle. Thecoating layer(s) can be used for controlled delivery of an active agentor a combination of active agents. In accordance with one embodiment,the method comprises (a) preparing a coating composition comprising oneor more polymers, one or more solvents and optionally one or moretherapeutic agents; (b) applying the coating composition onto a medicaldevice to form a wet coating layer; and (c) subjecting the wet coatinglayer to a freeze-thaw cycle.

The freeze part of the cycle can comprise dipping the medical device inliquid nitrogen. In some embodiments, at least an amount of thesolvent(s) can be removed prior to the freeze-thaw cycle.

In accordance with another embodiment, the method comprises (a)preparing a coating composition comprising one or more polymers, and oneor more solvents and optionally one or more active agents; (b) applyingthe coating composition onto a medical device to form a wet coatinglayer; (c) removing the solvent(s) to form a dry coating layer, the drycoating layer having less than 2% solvent(s); and (d) subjecting the drycoating layer to a freeze-thaw cycle.

In accordance with another embodiment, the coating on the device issubjected to a freeze-thaw cycle using an oven or chamber withtemperature control and temperature cycling capabilities.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a graph showing a release rate profile according to theExample.

DETAILED DESCRIPTION

As discussed in further detail below, the present invention generallypertains to coating layer or layers for medical devices, particularlyimplantable medical devices, comprising a polymer matrix and one or moreactive agents. The present invention also provides methods for formingcoating layer(s) for medical devices comprising a polymer matrix and oneor more active agents, where it is believed that the morphology of thecoating layer and/or the phase state of the active agent within thelayer are controlled by process parameters. Further, the presentinvention pertains to methods for controlling the morphology of acoating layer and/or the release-rate of an active agent from the layer.

It is believed that by controlling the morphology of the coating layerduring formation, and particularly the active agent phase state withinit, the release-rates of the active agent from the coating layer can bemore effectively controlled and manufacturing inconsistencies reduced oreliminated. Thus, improved therapeutic, prophylactic or other biologicaleffects may be realized in the treatment of a subject. The use ofprocess parameters in the methods of the present invention instead ofadditional excipients to control active agent release-rates providesadvantages in the design of controlled release systems. Further, thecontrol of active agent release-rates has positive implications for themechanical integrity of the polymeric matrix, as well as a relationshipto a subject's absorption rate of absorbable polymers.

There are many considerations in designing, controlling or predictingthe active agent release-rates from a coating layer comprising a polymermatrix and one or more active agents. These include, but are not limitedto, the morphology of the coating layer and components in the layer; thesize and shape of the active agent; the active agent phase and thedistribution of phases in the layer; the selection and the concentrationof active agent or agents; the presence of polymorphism of the agents;the polymer or polymers forming the polymer matrix; the presence offunctional groups on the polymers; the hydrophilicity or hydrophobicityof the polymer matrix; the presence of other additives in thecomposition, for example, fillers, metals, plasticizing agents,cross-linking agents; and the degree, if any, of bonding between thepolymer matrix and the active agent(s).

The morphology of the coating layer is particularly important indetermining the performance characteristics of the coating layer,because the distribution of an active agent and the phases of the activeagent within the polymer matrix directly relate to the active agentrelease-rate profile. In particular, a goal is controlling thepolymer-matrix-active-agent morphology within the coating layer(s) toprovide layer(s) with predictable active agent release-rates. It isbelieved that the methods of the present invention use processparameters to control coating layer morphology and phase state of theactive agent in the polymer matrix. The methods of the present inventioncan decrease active agent release-rates. A further aspect of the presentinvention provides methods for enhanced process control and coatingreproducibility for medical articles and devices comprising a polymermatrix and one or more active agents.

The term “morphology” as used herein refers to the way in which apolymer matrix, optionally active agent(s), and optionally othercomponents, lie in a coating layer after solvent removal. The morphologycan be defined in terms of properties such as the shape, structure, formor phase of components in the coating layer. The term “configuration” isalso used herein to refer to the morphology of the coating layer. Inparticular, morphology is used herein to describe the arrangement of thephase(s) or phase state or distribution of the active agent in thepolymer matrix and the distribution of those phases within the coatinglayer.

The morphology of the coating layer can be defined, for example, by thepresence and characteristics of phase separation between componentswithin the coating, where the phase separation can exist betweenpolymers of the matrix, an agent and a polymer, between agents, orbetween other components in the polymeric matrix. In one embodiment, thecoating layer morphology is defined by the phase state or distribution,or phase(s) of the active agent within the polymer matrix. In otherembodiments, the morphology can be defined, for example, by thecharacteristics of the zone of phase separation, where the zone of phaseseparation can be thin, thick, continuous, non-continuous, hydrophobic,hydrophilic, porous, interconnected, dispersed, and the like. In someembodiments, the morphology can be defined, for example, by otherphysical characteristics of the polymeric matrix including, but notlimited to, the presence of pores, crystalline or semi-crystallineregions, amorphous regions, metals, ceramics, the existence ofpolymorphism in agents, and the like. Any coating property that would beconsidered a morphological characteristic to one of skill in the art iswithin the scope of the present invention. The morphology can becharacterized by any method or measurement known in the art tocharacterize layers comprising polymers.

The “phase” of components of the coating layer can be defined by thecrystallinity, semi-crystallinity, liquid crystallinity, orientation, orpolymorphic state of the component, for example. The term “phase state”is used to refer to the phases of a component in the coating layer,particularly when the component is present in more than one phase. Inparticular, phase state is used to refer to the phase distribution ofactive agent in a coating layer. In one embodiment, the phase state ofthe active agent in the coating layer comprises one or more phases.

The formation of an active agent phase depends on the thermodynamics andkinetics of processing. Kinetics of processing can be further subdividedinto internal kinetic time constants and external time constants.Internal time constants include, for example, crystallization andmigration rate of active agents. External time constants include, forexample, the rate of solvent removal from the wet coating layer.

The methods and embodiments of the present invention are most usefulwhere the active agent is blended with, dissolved in, impregnated,trapped or distributed in the polymer matrix. This means the activeagent exists molecularly, at a molecular size, surrounded by polymermolecules of the polymer matrix. In some of these types of embodiments,the active agent is not covalently attached to the polymer matrix. Therelease, and hence the release-rate, of the active agent from thecoating layer depends on the ability of the active agent to diffusethrough the polymer matrix. This diffusion depends on the active agentphase in the layer and the transport properties of the polymeric matrix.It is one of the goals of the present invention to modulate or controlthe active agent phase and hence control the release-rate of the activeagent from the coating layer.

In some embodiments, the active agent exists in the coating layer in adissolved, dispersed or percolated phase. A coating layer can comprisesome fraction of all three active agent phases. Without being bound byany particular theory, it is believed that the ratio of the co-existingphases is a function of the volume fraction of active agent to polymerin the coating layer, as well as the active agent's physicochemicalproperties, such as its solubility in the polymer matrix. Thus, at lowactive-agent-to-polymer ratios, for example below about 10% by volumefraction active agent to polymer, the active agent phase willpredominantly be a dissolved phase. As the percentage of active agentincreases, the fraction of the other phases mixed with the dissolvedphase increases.

In one embodiment, the active agent of the coating layer is in adissolved phase. In one embodiment, the active agent of the coatinglayer is in a dispersed phase. In one embodiment, the active agent ofthe coating layer is in a percolated phase. In one embodiment, theactive agent of the coating layer comprises a mixed phase, wherein thephase state comprises two or more phases selected from the groupconsisting of dissolved, dispersed, or percolated phases. In oneembodiment, the active agent phase state comprises dissolved phase,dispersed phase and percolated phase. In one embodiment, the activeagent phase state is primarily dissolved phase. In one embodiment, theactive agent phase state is primarily dispersed phase. In oneembodiment, the active agent phase state is primarily dissolved anddispersed phases. The percentage of an active agent phase present in acoating layer can be controlled by the methods described herein.

As used herein, dissolved phase refers to an active agent phase in whichthe active agent is dissolved in the solid polymer matrix as in a solidsolution. In other words, the active agent species are not closelyassociated with other active agent species within the coating layer andare surrounded by polymer molecules of the polymer matrix. Dissolvedphases occur particularly at low active agent concentrations, where theconcentration is measured as a volume fraction of the active agent topolymer in the coating layer—for example at concentrations below about10% by volume fraction of active agent to polymer in the coating layer,and also in coating layers where no phase separation occurs between thesolvent, polymer matrix and active agent. Additionally, the presence ofdissolved phase depends on the active agent solubility in polymer matrixpolymers. At higher volume fractions, the dissolved phase usuallyco-exists with other active agent phases. In one embodiment, the amountof dissolved phase in the coating layer is equal to or greater than theamount of either dispersed or percolated phase. The phase ratiosdepending on, for example, the active agent concentration, the degree ofphase separation, and the active agent solubility in polymer matrixpolymers.

At active agent concentrations of about 10% or greater by volumefraction of active agent to polymer the active agent may coalesce toform a dispersed phase. As used herein, a dispersed phase refers to aphase where a number of active agent species coalesce to form activeagent particles or clusters throughout the coating layer that aresurrounded by polymer matrix polymer molecules. Dispersed phases canalso form at lower concentrations depending on the solubility of activeagent in the polymer matrix.

As used herein, percolated phase refers to an active agent phase whereactive agent molecules significantly migrate and/or phase separate inthe polymer matrix during formation of the coating layer formingconnected pathways of active agent throughout the polymer. When theactive agent is present in the percolated phase, there is less controlover the active agent release-rate than when the active agent is in thedissolved or dispersed phase, because the random connected pathways ofactive agent provide a means for the active agent to diffuse out of andbe released from the coating layer. Thus, the presence of percolatedactive agent phase has a significant effect on the release-rate of theactive agent from the coating layer. The presence of percolated phaseincreases the active agent release-rate. The mass transport propertiesof active agents are distinct through the percolation phase. The masstransport through the percolation phase is driven by the solubility ofactive agent in the release medium, the diffusivity of the active agentin the release medium, and the morphological feature of the percolatedphase such as, for example, tortuosity and area fraction. The percolatedphase is most often observed at active agent concentrations of about 35%or greater by volume fraction of active agent to polymer in the coatinglayer, but may also form at lower concentrations depending on thesolubility of the active agent in the polymer matrix and other factorssuch as active agent aspect ratio or morphology and active agent-polymerinterfacial properties. The active agent concentration at whichpercolated phase becomes the predominant phase is referred to herein asthe “percolation threshold.” The active agent concentration at which thepercolation threshold is observed depends on factors including, forexample, the choice of active agent, polymer matrix and solvent, as wellas those described below. In some embodiments of the present invention,the concentration of active is at the percolation threshold and theactive agent is primarily in a phase other than the percolated phase.

Percolate phase formation kinetics depend on a number of factorsincluding the active agent concentration, the solvent phase, the solventused, the mobility of active agent, the temperature at which solvent isremoved, the method of removing solvent and other processes conditions,such as the environment in which drying occurs. By using the methodsdescribed herein to fix the active agent phase in a desired phase orphase state before solvent removal, the degree of phase separation anddispersion of active agent within the polymer matrix can be controlled.Thus, a phase state profile and morphology of the coating layer can becreated that provides a controllable release-rate profile for the activeagent. Further, by fixing the active agent in a dissolved or dispersedphase at higher active agent concentrations more control on therelease-rate is obtained because formation of percolated phase isprevented or greatly reduced. In one embodiment, percolated phaseformation kinetics at high active agent concentrations are controlled byfixing the active agent phase state after coating a device with acoating composition. Another aspect of the present invention is tocontrol or prevent concentration gradients of active agents from formingin the coating layer, by fixing the active agent phase state beforeremoving solvent from the wet coating layer.

The coating layer or layers of the present invention comprise a polymermatrix, including one or more polymers and one or more active agents.Optionally, the coating layer may further comprise one or more additivesor other components. In addition to the polymer/drug layer, the coatinglayers can include any number of other layers including primer layer,other drug/polymer layer(s), topcoat layer or finishing coating or anycombination of these layers.

The drug coating layer(s) can be formed by blending one or more activeagents together with one or more polymers dissolved in one or moresolvents to form a coating composition, applying, such as by spraying ordipping, the coating composition to a medical device surface or onto aprimer layer, and removing the solvent(s) to leave on the device activeagent(s) dispersed in a polymer matrix. The morphology of the coatinglayer comprising a polymer matrix and one or more agents, and the phasestate of the active agent within that layer, and hence the agentrelease-rate from the layer, can be profoundly affected by the manner inwhich the coating layer is formed and the solvent is removed from thecoating composition to form a coating layer. When solvent is removedduring drying, active agent dispersion and configuration within thecoating layer can change due to phase separation between the solvent,and the polymer and active agent phase. This results in a coating layermorphology and distribution of active agent that is difficult to predictand control.

One embodiment of the present invention provides methods to control thecoating layer morphology by fixing the active agent morphology before,during and or after solvent removal from the coating composition. Insome of these embodiments, solvent removal forms a dried coating layer.Dried coating is defined as less that 2% residual solvent. In someembodiments, it is defined as less than 1% residual solvent. In someembodiments, it is defined as 0% solvent, i.e., all of the solvent iscompletely removed. Yet in some embodiments, dried coating can includean insignificantly nominal amount of solvent remaining, such as 0.1% orless.

The coating composition after being deposited on a device surface isreferred to as a “wet coating layer.” As used herein the term “wetcoating layer” refers to a coating composition comprising solvent thathas been applied to the device. “Wet” can be defined as opposite of thedry coating as defined above or, in other words, a coating layer isreferred to as wet until essentially all the solvent is removed from thecoating layer. In some embodiments, wet is defined as including all ofthe solvent (100%) or over 90% of the solvent. In some embodiments, itis defined as including over 80%, 70%, 60% or 50% (“majority”) of thesolvent. In the embodiments of the present invention, solvent in a wetcoating layer may not necessarily be in a liquid state. In oneembodiment, the method of the present invention is conducted when thecoating is wet, when the coating is dry, or at each step. In otherembodiments, a fraction of solvent is removed before the morphology ofthe polymer matrix and active agent is fixed. This removal helpsmodulate the degree of phase separation and the distribution of activeagent phases in the layer, and hence helps control the active agentrelease-rate. The present invention is especially useful forcompositions with a high active-agent-to-polymer ratio, where phaseseparation or percolated phase formation are more likely. The methods ofthe present invention may further control or modulate the development ofactive agent concentration gradients within the polymer matrix.

It is believed that the coating layers provide for less variablerelease-rates of active agents from the coatings layers. While not beingbound by any theory, apparently the fixing process renders the coatinglayer's thermo-mechanical and morphological properties less sensitive tosubsequent processing. Apparently, controlling coating layer morphology,and hence active agent release-rates, can control or eliminatemanufacturing inconsistencies.

Methods of Forming Coating Layers

The present invention provides methods for forming a coating layer for amedical device with a controlled active agent morphology. In oneinvention embodiment, fixing the active agent phase state while formingthe coating layer controls the active agent release-rate. In someembodiments, controlling the release rate means reducing the releaserate as compared to if the modification was not performed on thecoating.

In some embodiments of the present invention, the method comprises:

-   -   (a) preparing a coating composition comprising one or more        polymers, one or more active agents, and one or more solvents;    -   (b) applying the coating composition onto a medical device to        form a wet coating layer;    -   (c) subjecting the wet coating layer to a freeze-thaw cycle; and    -   (d) removing the one or more solvents from the wet coating layer        to form a coating layer.

In some embodiments of the present invention, the method comprises:

-   -   (a) preparing a coating composition comprising one or more        polymers, one or more active agents, and one or more solvents;    -   (b) applying the coating composition onto a medical device to        form a wet coating layer;    -   (c) removing a fraction of the one or more solvents from the wet        coating layer;    -   (d) subjecting the wet coating to a freeze-thaw cycle; and    -   (e) removing the remaining solvent(s) to form a coating layer.

In some embodiments of the present invention, the method comprises:

-   -   (a) preparing a coating composition comprising one or more        polymers, one or more active agents, and one or more solvents;    -   (b) applying the coating composition onto a medical device to        form a wet coating layer;    -   (c) removing the solvent(s) to form a dry coating layer; and    -   (d) subjecting the dry coating layer to a freeze-thaw cycle.

The various embodiments described above can include applying one or morepolymer layers, with or without a drug, over the layer including the oneor more agents such that the freeze-thaw cycle is performed beforeand/or after the formation of such layers. Embodiments of the presentinvention may further comprise one or more optional post-formationprocess steps. For example, post-formation process steps include, butare not limited to, annealing the coating layer, applying an optionalfinishing coat layer, and sterilization. Other post-process steps orcombinations of post-process steps may also be used in the practice ofthe invention.

The freeze-thaw cycle comprises applying a cold liquid to the wet or drycoating following by heating the coating. The freeze part of the cyclecan be conducted by a cold inert gas or fluid such as liquid nitrogen,dry ice (CO₂), liquid argon, or liquid ammonia. The gas can bedischarged onto the coating or the coating can be dipped into acontainer of the liquid. Freeze-thaw cycling can be successfullyconducted in temperature cycling ovens or chambers which are hooked upto liquid nitrogen storage tanks and have the necessary elements tochange from very cold to very hot temperatures with excellenttemperature control capabilities. In this way, hundreds or thousands ofstents can be subjected to the regimen at one time. Minimum or nophysical contact, such as by a substrate, a part of a device, mouldingor apparatus, with the coating is desired to prevent damage to thecoating. In a preferred embodiment, the wet or dry coating on the deviceis dipped into a container of liquid nitrogen. The coating compositioncan be cooled to a temperature of 10° C. or less, alternatively 0° C. orless, −10° C. or less, −20° C. or less, −30° C. or less, −40° C. orless, −50° C. or less, −100° C. or less, −150° C. or less, and −180° C.or less. In some embodiments, the temperature has to be equal or belowthe freezing temperature of a solvent used. The duration of exposure canbe from 1 second to 5 minutes. In some embodiments, it can be less than1 minute. In some embodiments, it can be from 1 second to 30 seconds.

The thaw portion of the cycle can be conduct by placing the device is anoven or by applying a warm gas to the device. The gas can be air,nitrogen or an inert such as argon. For the application of the gas, itis preferred that the gas be applied evenly across the surface of thedevice. For stent applications, this can be accomplished by the distanceof the gas nozzle from the stent and rotation of the stent during thegas application process. The temperature during the thaw portion of thecycle can be from about 25° C. to 300° C. In some embodiments, it shouldbe not more than 150° C., not more than 100° C., not more than 75° C.,or not more than 50° C. In some embodiments, the temperature can be 50°C.+/−3° C. The duration of the thaw cycle can be from 10 seconds to 2hours. In some embodiments, it can be less than 1 minute, such as 30seconds. The freeze-thaw cycle can be a single cycle or multiple cyclessuch as 2 or 3 cycles. In some embodiments, the condensation formed onthe coating should be removed such as by physically agitating the stentby motions including taping, shaking or the like. Condensation can beremoved during and/or after the thaw portion of the cycle.

When the freeze-thaw cycle is applied to a wet coating, subsequentsublimation or other suitable methods can be used to remove anyremaining solvent.

Another aspect of the present invention is to control the fraction ofsolvent removed from the wet coating layer before the freeze-thaw cycle.By removing a known solvent fraction after applying the coatingcomposition, the morphology of the polymer-matrix-active-agent coatinglayer can be designed to have a selected amount of phase separationbetween the solvent and the polymer matrix and active agent phase, andthus a predetermined fraction of an active agent phase. Hence, theactive agent release-rate can be modified for the most beneficialtherapeutic effect in a subject. In some embodiments, between about 1and 90%, alternatively, between about 1 and 80%, about 1 and 70%, about1 and 60%, about 1 and 50%, about 1 and 25%, or about 1 and 10%, byweight of the solvent in the coating composition is removed from thecoating layer before the polymer-matrix-active-agent configuration inthe coating layer is subjected to the freeze-thaw cycle.

The percentage of an active agent phase present in a coating layer canbe selected by the methods described herein. The amount of a particularactive agent phase present in the coating layer can vary considerablyover the range from 0% to 100% based in the total amount of active agentin the coating layer. In some embodiments, the ration of polymer:drug(w/w) can range from 50:1 to 1:50. In some embodiments the followingpolymer:drug ranges are applicable: 1:1; 2:1; 3:1; 4:1; 5:1; 6:1: 7:1;8:1; 9:1; 10:1; 1:2; 1:3; 1:4; 1:5; 1:6; 1:7; 1:8; 1:9; 1:10; or betweenany combination of such ranges. In one embodiment, the percentage ofdissolved phase is greater than the combined amount of dispersed andpercolated phase. In other embodiments, the percentage of dissolvedphase is equal to or greater than the percentage of either dispersed orpercolated phase in the coating layer. In yet other embodiments, thepercentage of dissolved phase is less than the percentage of dispersedor percolated phase in the coating layer. Designing the percentage ofactive agent in different phases can select the most therapeuticallyeffective release-rate. In some embodiment, the release-rate profile ofactive agent from the coating layer is determined by the ratio of thephase states of the active agent in the coating layer.

Coating layer thickness is from about 0.1 nm to about 1.0 cm, from about0.1 nm to about 1.0 mm, from about 0.1 nm to about 100 μm, from about0.1 nm to about 1 μm, from about 0.1 nm to about 100 nm, from about 0.1nm to about 10 nm, from about 10 nm to about 100 nm, from about 0.5 μmto about 10 μm, from about 1 μm to about 10 μm, from about 10 μm toabout 50 μm, from about 50 μm to about 100 μm, or any range therein. Inother embodiments, the thickness of the coating layer can be regionallydistributed throughout a device to create a variation in thicknessessuch as, for example, the variation in thicknesses present in anabluminally-coated drug-eluting stent (DES) systems.

Coating Compositions

The coating compositions of the present invention comprise one or moreactive agents (optional for example for topcoat modification), one ormore polymers, and one or more solvents. Optionally, the coatingcomposition may further comprise one or more additives or othercomponents such as, for example, plasticizing agents, metals, metaloxides or ceramics.

Coating compositions are prepared by conventional methods, wherein allcomponents are combined and then blended. More particularly, adding apredetermined amount of polymer to a predetermined amount of acompatible solvent forms a polymer solution. The polymer can be added tothe solvent at ambient pressure, and under anhydrous or otheratmosphere. If necessary, gentle heating and stirring or mixing cancause the polymer to dissolve into the solvent, for example, 12 hours ina 60° C. water bath.

Sufficient amounts of active agent are dispersed in the blended polymersolution. The active agent preferably should be in true solution orsaturated in the blended composition. If the active agent is notcompletely soluble in the composition, operations including mixing,stirring, or agitation can be employed to homogenize the residuals.Alternatively, active agent can first be added to a compatible solventbefore mixing with the polymer solution. Optionally, a second solvent,such as tetrahydrofuran or dimethylformamide, can be used to improve thesolubility of an active agent in the coating composition or to increasethe composition's wetting ability. The second solvent can be added tothe coating composition or the active agent can be added to the secondsolvent before mixing with the polymer solution.

If additives and other components, for example cross-linking agents,plasticizers, or ceramics, are used these may be added and blended withthe coating composition at any step.

The amount of active agent in the coating layer should be the dosage orconcentration required to produce a therapeutic effect, and greater thanthe level at which non-therapeutic results are obtained. The dosage orconcentration of the active agent depends upon factors such as, forexample, the particular circumstances of the subject, the nature of thetrauma, the nature of the therapy desired, the time over which theingredient administered resides at the vascular site, and if otherbio-active substances are employed, the nature and type of the substanceor the combination of substances. The therapeutically effective dosagecan be determined by methods known in the art, such as for example,conducting suitable in vitro studies.

The one or more polymers of the polymer matrix can comprise from about0.1% to about 35%, and more narrowly from about 2% to about 20% byweight of the total weight of the coating composition. The one or moresolvents may comprise from about 19.8% to about 99.8%, more narrowlyfrom about 49% to about 87%, and yet more narrowly from about 79% toabout 87% by weight of the total weight of the coating compositions. Theone or more active agents may comprise from about 0.02% to about 40%,preferably from about 0.1% to about 9%, and more narrowly from about0.7% to about 1.2% by weight of the total weight of the coatingcomposition. Selection of a specific weight ratio of the polymer andsolvent depends on factors such as, but not limited to, the materialfrom which the device is made, the geometrical structure of the device,and the type and amount of active agent employed. The specific weightpercent of active agent depends on the polymer matrix-active agentmorphology of the coating layer and phases of active agent required, andfactors such as the dosage, duration of the release, cumulative amountof release, and the release-rate desired.

The coating layers of the present invention comprise a polymer matrix,composed of one or more polymers. The one or more polymers comprisingthe polymer matrix may be in mixed, blended or conjugated form. Thepolymer matrices and coating compositions of the present invention mayalso be used to form medical devices by a process such as, for example,molding.

There is a wide choice of polymer and copolymers for use in the polymermatrix of the present invention. The chosen polymer matrix must be onethat is biocompatible and minimizes irritation when implanted. Thechoice of the matrix components depends on numerous factors including,but not limited to, the interactions between the polymer(s) and theagent(s) and/or solvent(s), the biocompatibility of the polymer(s), andthe physical, mechanical, chemical and biological properties of thepolymers. Performance parameters include, for example, the ability toadhere to the surface of the medical device, the toughness of thecoating desired, the capacity for the loading concentration of an agent,and the rate of biodegradation and elimination of the composition from asubject.

Each of the one or more polymers chosen for the matrix can be eitherbiostable or biodegradable. “Biodegradable” refers to polymers that arecapable of being completely degraded and/or eroded when exposed tobodily fluids such as blood and can be gradually resorbed, absorbedand/or eliminated from the subject. The term biodegredable is usedinterchangeably with bioerodable and bioabsorbable. The process ofbreaking down and eventual absorption and elimination of the polymer canbe caused by, for example, hydrolysis, metabolic processes, bulk orsurface erosion, and the like. After biodegradation traces or residualpolymer may remain on the device or near the device. Examples ofbiodegradable polymers include, but are not limited to, polymers havingrepeating units such as, for example, an α-hydroxycarboxylic acid, acyclic diester of an α-hydroxycarboxylic acid, a dioxanone, a lactone, acyclic carbonate, a cyclic oxalate, an epoxide, a glycol, an anhydride,a lactic acid, a glycolic acid, a lactide, a glycolide, an ethyleneoxide, an ethylene glycol, or combinations thereof. In some embodiments,the polymer matrix releases active agent during biodegradation. In otherembodiments, the polymer matrix releases active agent withoutbiodegradation of the matrix. In yet other embodiments, the release ofactive agent may be partially dependent on biodegradation of the polymermatrix. Biostable polymers should have a relatively low chronic tissueresponse.

The polymers useful for the polymer matrixes of the present inventioninclude, but are not limited to, natural or synthetic polymers,condensation polymers, homopolymers and copolymers or any combinationand/or blend thereof. Polymers may be hydrophobic, hydrophilic, or acombination thereof. Copolymers may be random, alternating, block,graft, and/or crosslinked, and may include polymers with more than twodifferent types of repeating units such as terpolymers. In someembodiments, the polymers are selected such that they specificallyexclude any one or any combination of any of the polymers taught herein.

Representative examples of polymers that can be used in the polymermatrices and coating compositions of the present invention include, butare not limited to, poly(acrylates) (such as poly(methacrylates),polymethyl methacrylate and polybutyl methacrylate), acrylic polymersand copolymer (such as polyacrylonitrile), poly(cyanoacrylates),fluorinated polymers or copolymers (such as polyfluoro-alkylenes,polyvinylidene fluoride-co-hexafluoropropene andpolytetrafluoroethylene), polycaprolactones, polylactides,poly(D-lactides), poly(L-lactides), poly(D,L-lactides), Poly(lacticacids), poly(glycolic acid), poly(lactide-co-glycolide), poly(glycolicacid-co-trimethylene carbonate), poly(lactic acid-co-trimethylenecarbonate, poly(amino acids), polyhydroxyalkanoates,poly(hydroxyvalerate), polyhydroxybutyrates,poly(hydroxybutyrate-co-valerate), polymers and copolymers ofhydroxylethyl methacryate, polydioxanones, polyorthoesters,polyanhydrides, polyphosphoesters, polyphosphoester urethanes,polyphosphazenes, polycarbonates, polyiminocarbonates, polytrimethylenecarbonates, co-poly(ether-esters) (such as polyethylene oxide/polylacticacid (PEO/PLA)), poly(alkylene oxalates), polyurethanes, silicones,polyesters, polyolefins (such as polyethylene and polypropylene),poly(isobutylene) and ethylene-alphaolefin copolymers, vinyl halidepolymers and copolymers (such as polyvinyl chloride), polyvinyl ethers(such as polyvinyl methyl ether), polyvinylidene halides (such aspolyvinylidene fluoride and polyvinylidene chloride), polyacrylonitrile,polyvinyl ketones, polyvinyl aromatics (such as polystyrene), polyvinylesters (such as polyvinyl acetate), copolymers of vinyl monomers witheach other and olefins (such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetatecopolymers), ethylene vinyl alcohol copolymers (such as ethylene vinylalcohol co-polymer, commonly know by the generic name EVOH or by thetrade name EVAL), polyamides (such as Nylon 66 and polycaprolactam),alkyd resins, polyoxymethylenes, polyimides, polyester amides,polyethers including poly(alkylene glycols) (such as poly(ethyleneglycol) and poly(propylene glycol)), poly(tyrosine derived carbonates),poly(tyrosine derived arylates), epoxy resins, rayon, rayon-triacetate,biomolecules (such as fibrin, fibrinogen, starch, cellulose, collagen,hyaluronic acid), poly(N-acetylglucosamine) (chitin), chitosan,cellulose, cellulose acetate, cellulose butyrate, cellulose acetatebutyrate, CELLOPHANE, cellulose nitrate, cellulose propionate, celluloseethers, and carboxymethyl-cellulose, and derivatives, copolymers andcombinations of the foregoing. In some embodiments, the polymer canexclude any one or any combination of the aforementioned polymers.

The solvent should be capable of dissolving the polymer at theconcentration desired in the coating solution. Solvents useful forforming the coating compositions of the present invention are chosenbased on factors such as, for example, the solubility of the one or morepolymers in the solvent, compatibility with the active agents, thevolatility of the solvent, and the ability of the solvent to be removedfrom the coating layer after the coating layer configuration is fixed.Any suitable solvent, or mixture of solvents, that meets the criteriafor a coating solvent can be used.

Examples of suitable solvents for the practice of the present inventioninclude, but are not limited to, dimethylacetamide, dimethylformamide,tetrahydrofuran, cyclohexanone, acetone, acetonitrile, i-propanol,n-propanol, methanol, ethanol, butanol, propylene glycol monomethylether, methyl butyl ketone, methyl ethyl ketone, diethyl ketone, ethylacetate, n-butyl acetate, dioxane, chloroform, water (buffered saline),dimethylsulfoxide, dimethylformide, benzene, toluene, xylene, hexane,cyclohexane, pentane, heptane, octane, nonane, decane, decalin, i-butylacetate, i-propyl acetate, diacetone alcohol, benzyl alcohol,1-butanone, 2-butanone, N-methylpyrrolidinone, methylene chloride,carbon tetrachloride, tetrachloroethylene, tetachloroethane,chlorobenzene, 1,1,1-trichloroethane, formamide, hexafluoroisopropanol,1,1,1-trifluoroethanol, hexamethyl phosphoramide, and combinationthereof.

The drug or therapeutic agent includes agents that haveanti-proliferative or anti-inflammatory properties or can have otherproperties such as antineoplastic, antiplatelet, anti-coagulant,anti-fibrin, antithrombogenic, antimitotic, antibiotic, antiallergic,antifibrotic, and antioxidant. The agents can be cystostatic agents,agents that promote the healing of the endothelium such as NO releasingor generating agents, agents that attract endothelial progenitor cells,agents that promote the attachment, migration or proliferation ofendothelial cells (e.g., natriuretic peptides such as CNP, ANP or BNPpeptide or an RGD or cRGD peptide), while impeding smooth muscle cellproliferation. Examples of suitable therapeutic and prophylactic agentsinclude synthetic inorganic and organic compounds, proteins andpeptides, polysaccharides and other sugars, lipids, and DNA and RNAnucleic acid sequences having therapeutic, prophylactic or diagnosticactivities. Some other examples of the bioactive agent includeantibodies, receptor ligands, enzymes, adhesion peptides, blood clottingfactors, inhibitors or clot dissolving agents such as streptokinase andtissue plasminogen activator, antigens for immunization, hormones andgrowth factors, oligonucleotides such as antisense oligonucleotides,small interfering RNA (siRNA), small hairpin RNA (shRNA), aptamers,ribozymes and retroviral vectors for use in gene therapy. Examples ofanti-proliferative agents include rapamycin and its functional orstructural derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),and its functional or structural derivatives, paclitaxel and itsfunctional and structural derivatives. Examples of rapamycin derivativesinclude 40-epi-(N-1-tetrazolyl)-rapamycin (ABT-578),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.Examples of paclitaxel derivatives include docetaxel. Examples ofantineoplastics and/or antimitotics include methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples ofsuch antiplatelets, anticoagulants, antifibrin, and antithrombinsinclude sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, thrombin inhibitorssuch as Angiomax (Biogen, Inc., Cambridge, Mass.), calcium channelblockers (such as nifedipine), colchicine, fibroblast growth factor(FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists,lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol loweringdrug, brand name Mevacor® from Merck & Co., Inc., Whitehouse Station,N.J.), monoclonal antibodies (such as those specific forPlatelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), nitric oxide or nitric oxidedonors, super oxide dismutases, super oxide dismutase mimetic,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), estradiol,anticancer agents, dietary supplements such as various vitamins, and acombination thereof. Examples of anti-inflammatory agents includingsteroidal and non-steroidal anti-inflammatory agents include tacrolimus,dexamethasone, clobetasol, mometasone, or combinations thereof. Examplesof cytostatic substances include angiopeptin, angiotensin convertingenzyme inhibitors such as captopril (e.g. Capoten® and Capozide® fromBristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril(e.g. Prinivil® and Prinzide® from Merck & Co., Inc., WhitehouseStation, N.J.). An example of an antiallergic agent is permirolastpotassium. Other therapeutic substances or agents which may beappropriate include alpha-interferon, pimecrolimus, imatinib mesylate,midostaurin, bioactive RGD, SIKVAV peptides, elevating agents such ascANP or cGMP peptides, and genetically engineered endothelial cells. Theforegoing substances can also be used in the form of prodrugs orco-drugs thereof. The foregoing substances also include metabolitesthereof and/or prodrugs of the metabolites. The foregoing substances arelisted by way of example and are not meant to be limiting. Other activeagents which are currently available or that may be developed in thefuture are equally applicable.

Application of Coating Composition onto a Medical Device.

Application of the coating composition onto the medical device can beaccomplished by any method known in the art. For example, the coatingcomposition may be applied to the medical device by casting, spraying,dipping or immersing, direct dispensing by hand or injection. Thecoating compositions of the present invention may be applied to all orto selected surfaces of a device.

Operations such as wiping, centrifugation, blowing or other web-clearingacts may be performed to achieve a more uniform coating. Briefly, wipingrefers to physical removal of excess coating from the surface of thedevice; centrifugation refers to the rapid rotation of the device aboutan axis of rotation; and blowing refers to application of air at aselected pressure to the deposited coating. Excess coating may also bevacuumed off the surface of the device.

Before applying the coating layer to a medical device, the surface ofthe device should be clean and free from contaminants that may be havebeen introduced during manufacture. However, no particular surfacetreatment is required prior to applying the coating composition.Metallic surfaces of stents can, for example, be cleaned by an argonplasma process as is known to one of ordinary skill in the art.

A primer layer may optionally be used in the embodiments of the presentinvention to aid the adhesion of the coating layer to the devicesurface. This is particularly useful when the presence or concentrationof the active agent in the polymer matrix interferes with the ability ofthe polymer matrix to adhere effectively to the device surface. If anoptional primer layer is used, the primer layer is coated on the deviceor a portion of the device by any method described herein or known toone of ordinary skill in the art. The primer layer is dried (solventremoved) or cured before the coating composition comprising the polymermatrix and active agent is applied to the surface of the primer layer.Primer compositions may be prepared by adding a predetermined amount ofone or more polymers to a predetermined amount of solvent or mixture ofsolvents. Representative examples of polymers for the primer layerinclude, but are not limited to, polyisocyanates, polyethers,polyurethanes, acrylates, titanates, zirconates, silane coupling agents,high amine content polymers, polymers with a high content of hydrogenbonding groups, and unsaturated polymers and prepolymers. Representativeexamples of polymers also include those polymers used in the polymermatrices of the present invention as described herein. Further examplesof primer layers useful for the medical devices of the present inventioninclude those disclosed in U.S. Pat. No. 6,908,624 to Hossainy et al.,the disclosure of which is incorporated herein by reference.

Drying Coating Compositions

After coating the medical device and before or after the freeze-thawcycle process, solvent remaining in the wet coating layer is removed toform a dry coating layer. It is understood that by drying substantiallyall the solvent will be removed from the coating layer, but traces orresidues can remain blended with the polymer. In order not to change thefixed morphology of the active agent in the coating layer, the selectedmethod should remove the solvent without causing undesired phaseseparations or phase changes. Suitable methods for removing the solventfrom the coating composition include, but are not limited to,evaporation, freeze-drying (sublimation), non-solvent exchange, criticalpoint drying, or any combination thereof. Removal of the solvent mayoccur in a controlled atmosphere, for example humid, anhydrous orsolvent saturated, at ambient pressure or under vacuum. The temperatureat which the solvent is removed will depend on the method, and may varyover a wide range.

In one embodiment of the present invention, solvent in the wet coatinglayer is removed by freeze-drying. The method comprises first freezingthe coating layer, if the layer is not already in a frozen state, andthen placing the medical device under reduced pressure or in a vacuum sothat the solvent molecules vaporize (sublime) without the solventpassing through a liquid phase. The rate at which the coating layer isfrozen and solvent removed may vary over a wide range. In oneembodiment, the coating layer is frozen to 0° C. or less, alternativelyto −40° C. or less, −70° C. or less, −100° C. or less, and −150° C. orless. In some embodiments, solvent removal is in essence accomplishedunder the freeze part of the freeze-thaw cycle of the present invention.

Evaporation of the solvent can occur at room temperature or be inducedby heating the device to a temperature for a period of time. Removal ofthe solvent may also occur in a controlled atmosphere, for examplehumid, anhydrous or solvent saturated, at ambient pressure or undervacuum. Conditions should be chosen so that they do not substantiallyadversely affect the active agent or the configuration of the activeagent. The coating layer can be heated at a temperature for a period oftime, for example, at 60° C. for 10 to 24 hours. The heating temperatureis chosen so as not to exceed temperatures at which the active agent isadversely affected.

In yet another embodiment of the present invention, solvent of thecoating layer can be removed from the coating layer by exchange with anon-solvent for the active agent, and subsequent removal of thenon-solvent. This can be accomplished, for example, by exposing the wetpolymer-matrix-active-agent coating layer to the non-solvent. The chosennon-solvent should be miscible with the solvent of the coatingcomposition. In some invention embodiments, the non-solvent issubstantially miscible with the coating composition solvent. Examples ofsuitable non-solvents for the active agents include, but are not limitedto, supercritical CO₂, isopropyl alcohol, acetone, heptane and hexane,and blends thereof. Other examples of suitable solvents include, but arenot limited to, fluorocarbons and chlorofluorocarbons, for exampleFreon™ and HCFC 141b (dichlorofluoroethane), and blends of fluorocarbonsand alcohol such as, for example, dichlorofluoroethane blended withethanol. Non-solvent exchange may be carried out, for example, by methodsuch as liquid, spray or vapor mist contact. In those embodiments wheresupercritical CO₂ is used as the non-solvent for the active agent, thecoating layer may be dried by critical point drying. In some embodimentsthe coating layers of the present invention are dried by critical pointdrying.

Post-Formation Processing Steps

After drying the coating layers by removing solvent from the wetcoating, post-freeze-thaw treatments may be performed to the coatinglayers and medical devices. Optional post-processing steps include, butare not limited to, annealing the coating layer, applying a protectivecoating, applying a rate-reducing membrane, diffusion barrier layer ortopcoat layer to the coating layer surface, applying an optionalfinishing coat layer, and sterilization. The medical devices may furthercomprise an optional top-coat or barrier layer that, in someembodiments, controls the diffusion of the active agent out of thecoating layer. Outer coating layers can be applied over all or only aportion of the coating layer comprising the active agent.

Medical Devices

Throughout this application “medical device” or “medical article” areused interchangeably, and refer to any device or article that can beused in the medical treatment of a human or veterinary subject. In someembodiments, the underlying medical device that is coated is a finishedproduct such that the device does not need any pre-coating manufacturingsteps. Medical devices may be used either externally on a subject orimplanted in a subject. In a preferred embodiment, the medical device isimplantable. An example of an implantable medical device is a stent,which can be implanted into a human or veterinary patient. Whileexamples of coating a device such as a drug eluting or delivery stentare described herein, one of skill in the art will appreciate that othermedical devices and substrates can be manufactured using the methods ofthe present invention. Examples of medical devices include, but are notlimited to, stent-grafts, vascular grafts, artificial heart valves,foramen ovale closure devices, cerebrospinal fluid shunts, pacemakerelectrodes, guidewires, ventricular assist devices, cardiopulmonarybypass circuits, blood oxygenators, coronary shunts vena cava filters,and endocardial leads. Examples of stents include, but are not limitedto, tubular stents, self-expanding stents, balloon expandable stents,coil stents, ring stents, multi-design stents, and the like. In someembodiments, the stents include, but are not limited to, vascularstents, renal stents, biliary stents, pulmonary stents andgastrointestinal stents.

The underlying structure of the medical device can be virtually anydesign. The medical device can be comprised of a metallic material oralloy, low-ferromagnetic, non-ferromagnetic, biostable polymeric,biodegradable polymeric, bioabsorbable polymers, biodegradable metallicor other compatible material known in the art. Examples of metals andalloys include, but are not limited to, ELASTINITE®, NITINOL® (NitinolDevices and Components, Fremont, Calif.), stainless steel, tantalum,tantalum-based alloys, nickel-titanium alloys, platinum, platinum-basedalloys such as, for example, platinum-iridium alloys, iridium, gold,magnesium, titanium, titanium-based alloys, zirconium-based alloys,alloys comprising cobalt and chromium (ELGILOY®, Elgiloy SpecialtyMetals, Inc., Elgin, Ill.; MP35N and MP20N, SPS Technologies,Jenkintown, Pa.) or combinations thereof. The trade names “MP35N” and“MP20N” describe alloys of cobalt, nickel, chromium and molybdenum. TheMP35N consists of 35% cobalt, 35% nickel, 20% chromium, and 10%molybdenum. The MP20N consists of 50% cobalt, 20% nickel, 20% chromium,and 10% molybdenum.

EXAMPLE

The following experiment was conducted to determine the effects of lowtemperature exposure on the drug recovery and drug releasecharacteristics of stents coated with Solef and EVAL. Two types ofcoating were used: Type 1 included PBMA primer and Solef/everolimus druglayer; and Type 2 included EVAL primer and EVAL/everolimus drug layer.

Group Number of Stents Used Type of Stent Freeze Cycle 1 6 Type 1 No 2 6Type 1 30 seconds in liquid nitrogen 3 6 Type 2 No 4 6 Type 2 30 secondsin liquid nitrogen

After coating and drying of the coating in an oven, the stents weredipped in liquid nitrogen followed by application of heat at about 50deg. C. (+/−3 deg. C.). The following procedure was followed: (1) Eachstent was numerically identified and placed individually on a hookstainless steel mandrel; (2) 200 ml liquid nitrogen was attained from astorage tank and placed into a 500 ml liquid nitrogen container; (3) thefirst group of four units were dipped simultaneously into the liquidnitrogen filled container and digitally timed for 30 seconds; (4) thefirst group was then removed and placed in front of a heated air flowhaving a temperature of 50 deg. C. for 30 seconds; (4) the procedure wasrepeated for the second group; and (5) the units were then placed incapped vials for stent testing. Condensation formed was removed bytapping and “whiffing” the mandrel.

The results are as follows:

Total content of everoliomus Total content % Relative (ug) (ug) % %Average Standard Group Sample # measured theoretical Recovery RecoveryDeviation 1 1 52.97 65.08 81.4 81.5 0.6 2 54.38 66.27 82.1 3 52.71 64.9281.2 2 4 52.47 65.93 79.6 80.5 1.1 5 53.85 66.27 81.3 6 53.34 66.10 80.73 7 83.92 135.00 62.2 62.3 0.5 8 81.85 130.75 62.6 9 78.45 126.50 62.0 410 81.83 126.00 64.9 64.2 2.1 11 78.84 125.75 62.7 12 80.69 124.00 65.1

FIG. 1 illustrates the release profile. As seen by the graph, therelease rate of everolimus from the chilled Type 1 stents is about onethird to that of the control. Everolimus also released more slowly fromthe chilled Type 2 group as compared to the control. Accordingly, thefreeze-thaw cycle slowed down drug release rate while not reducing drugrecovery.

While particular embodiments of the present invention have beendescribed, it will be obvious to those skilled in the art that changesand modifications can be made without departing from the spirit andscope of the teachings and embodiments of this invention. One skilled inthe art will appreciate that such teachings are provided in the way ofexample only, and are not intended to limit the scope of the invention.Therefore, the appended claims are to encompass within their scope allsuch changes and modifications as fall within the true spirit of thisinvention.

The invention claimed is:
 1. A method comprising: (a) preparing acoating composition comprising one or more polymers, one or moresolvents and optionally one or more therapeutic agents; (b) applying thecoating composition onto a medical device to form a wet coating layer;(c) removing a selected amount of the one or more solvents from the wetcoating layer prior to subjecting the wet coating layer to a freeze-thawcycle; (d) subjecting the wet coating layer to the freeze-thaw cycle;and (e) subsequent to the freeze-thaw cycle, removing the remainder ofthe one or more solvents.
 2. The method of claim 1, wherein the freezepart of the cycle comprises dipping the medical device in liquidnitrogen.
 3. The method of claim 1, wherein the thaw part of the cyclecomprises exposing the medical device to a gas at a selected thawtemperature.
 4. The method of claim 1, additionally comprising removingcondensation from the coating layer during or after the thaw part of thecycle.
 5. The method of claim 1, wherein the freeze part of the cyclecomprises dipping the medical device in a bath of dry ice, liquid argon,or liquid ammonia.
 6. The method of claim 1, wherein the coatingcomposition does not include any therapeutic agents.
 7. The method ofclaim 1, wherein the medical device is a stent.
 8. The method of claim1, wherein the coating composition does not include any therapeuticagents and forms a topcoat over a drug-reservoir layer.
 9. A stenthaving a coating produced in accordance with the method of claim
 1. 10.The method of claim 1, wherein the freeze part of the cycle comprisesexposing the medical device to a gas at a selected freeze temperature.11. The method of claim 1, wherein removing the remainder of the one ormore solvents comprises evaporation.
 12. The method of claim 1, whereinremoving the remainder of the one or more solvents comprisesfreeze-drying.
 13. The method of claim 1, wherein removing the remainderof the one or more solvents comprises non-solvent exchange.
 14. Themethod of claim 1, wherein removing the remainder of the one or moresolvents comprises critical point drying.
 15. The method of claim 1,wherein after removing the remaining one or more solvents, the medicaldevice is sterilized.
 16. The method of claim 1, wherein at least one ofthe one or more solvents is selected from the group consisting ofdimethylacetamide, dimethylformamide, tetrahydrofuran, cyclohexanone,acetone, acetonitrile, i-propanol, n-propanol, methanol, ethanol,butanol, propylene glycol monomethyl ether, methyl butyl ketone, methylethyl ketone, diethyl ketone, ethyl acetate, n-butyl acetate, dioxane,chloroform, dimethylsulfoxide, dimethylformide, benzene, toluene,xylene, hexane, cyclohexane, pentane, heptane, octane, nonane, decane,decalin, i-butyl acetate, i-propyl acetate, diacetone alcohol, benzylalcohol, 1-butanone, 2-butanone, N-methylpyrrolidinone, methylenechloride, carbon tetrachloride, tetrachloroethylene, tetachloroethane,chlorobenzene, 1,1,1-trichloroethane, formamide, hexafluoroisopropanol,1,1,1-trifluoroethanol, and hexamethyl phosphoramide.
 17. A methodcomprising: (a) preparing a coating composition comprising one or morepolymers, and one or more solvents; (b) applying the coating compositiononto a medical device to form a wet coating layer; (c) removing aselected amount of the one or more solvents from the wet coating layerprior to the freeze-thaw cycle; (d) subjecting the wet coating layer toa freeze-thaw cycle; and (e) subsequent to the freeze-thaw cycle,concurrent with the freeze-thaw cycle, or a combination of subsequent toand concurrent with the freeze-thaw cycle, removing the remainder of theone or more solvents; wherein the coating composition forms a topcoatover a drug-reservoir layer.
 18. A method comprising: (a) preparing acoating composition comprising one or more polymers, one or moresolvents and optionally one or more therapeutic agents; (b) applying thecoating composition onto a medical device to form a wet coating layer;(c) removing a selected amount of the one or more solvents from the wetcoating layer prior to the freeze-thaw cycle; (d) subjecting the wetcoating layer to a freeze-thaw cycle; and (e) subsequent to thefreeze-thaw cycle, concurrent with the freeze-thaw cycle, or acombination of subsequent to and concurrent with the freeze-thaw cycle,removing the remainder of the one or more solvents; wherein removal ofthe remainder of the one or more solvents comprises evaporation,non-solvent exchange, critical point drying, or a combination thereof.19. The method of claim 18, wherein removing the remainder of the one ormore solvents comprises evaporation.
 20. The method of claim 18, whereinremoving the remainder of the one or more solvents comprises non-solventexchange.
 21. The method of claim 18, wherein removing the remainder ofthe one or more solvents comprises critical point drying.